Summary We investigated whether a single 60‐min bout of whole leg, peristaltic pulse external pneumatic compression (EPC) altered select growth factor‐related mRNAs and/or various phospho(p)‐proteins related to cell growth, proliferation, inflammation and apoptosis signalling (e.g. Akt‐mTOR, Jak‐Stat). Ten participants (8 males, 2 females; aged 22·2 ± 0·4 years) reported to the laboratory 4 h post‐prandial, and vastus lateralis muscle biopsies were obtained prior to (PRE), 1 h and 4 h post‐EPC treatment. mRNA expression was analysed using real‐time RT‐PCR and phosphophorylated and cleaved proteins were analysed using an antibody array. No changes in selected growth factor‐related mRNAs were observed following EPC. All p‐proteins significantly altered by EPC decreased, except for p‐rps6 (Ser235/236) which increased 31% 1 h post‐EPC compared to PRE levels (P = 0·016). Notable decreases also included p‐BAD (Ser112; −28%, P = 0·004) at 4 h post‐EPC compared to PRE levels. In summary, an acute bout of EPC transiently upregulates p‐rps6 as well as affecting other markers in the Akt‐mTOR signalling cascade. Future research should characterize whether chronic EPC application promotes alterations in lower‐limb musculature and/or enhances exercise‐induced training adaptations.